TrustTheEvidence.net

Are placebos as good as ‘real’ antidepressant drugs?

Dr Placebo — Mon, 20 Feb 2012 17:27:52 +0000

The National Health Service in the United Kingdom spends over 300 million pounds per year on antidepressants (475 million USD).

Yet in a large study comparing antidepressant drugs with placebos, Irving Kirsch found no significant difference between placebos and ‘active’ drugs except for patients with severe depression.

Last Sunday night the research was discussed in a CBS 60 Minutes report. During her interview, reporter Lesley Stahl challenged Kirsch: "You're saying if (patients taking antidepressants) took a sugar pill, they'd have the same effect?"

Kirsch replied: "They'd have almost as large an effect, and whatever difference it would be, would be clinically insignificant."

Stahl was incredulous. "But people are getting better taking antidepressants, I know them. We all know them."

"People get better when they take the drug, but it's not the chemical ingredients of the drugs that are making them better. It's largely the placebo effect," Kirsch replied.

Kirsch’s research raises many provocative questions. If placebos appear to cure depression, is depression a real disease? How can a sugar pill cure depression? If sugar pills work as well as drugs and have fewer side effects, why not use them?

Nobody doubts that depression can be very serious. (And any patient taking or considering antidepressant medication should consult a qualified practitioner before making treatment decisions.) Instead, it means placebos are particularly good at curing depression. This can be achieved through several mechanisms. The sugar in the pill can influence insulin levels and induce a cascade of physiological effects. Moreover the doctor’s friendly manner, also part of the placebo, has been shown to make mildly depressed patients feel better.

The reason placebos aren’t prescribed is doctors deem them to be unethical. This is because (among other reasons) doctors should only prescribe treatments that are proven to be effective. But effectiveness is often established by demonstrating superiority to placebos; so to prove they are effective, then need to be more effective than themselves, which is impossible. Moreover, as Stahl noted, the ‘real’ drugs have known and serious side effects. So not prescribing placebos might be even less ethical.

Whatever the answers to these difficult questions, surely we can come up with an answer to the placebo ethics dilemma that costs less than 300 million pounds per year. More research, please!

EBM at the bedside-bicuspid aortic valves and familial screening

Ami Banerjee — Fri, 20 Jan 2012 12:29:10 +0000

The original proponents of EBM have always argued for “evidence at the bedside” so that we can make the best decisions for patients nearest to the point “where the rubber hits the road”. How often do we clinicians actually look up the evidence in real time during or soon after a consultation to change the management or the advice we give to a patient?

I saw a lady in her 40s in our cardiology clinic this week. She has been followed up every 1-2 years in clinic for bicuspid aortic valve (BAV). Basically, the aortic valve is at the outflow of the left ventricle (the major pump of the heart) and usually has three cusps which open and close to ensure flow of blood in the right direction through and out of the heart. In bicuspid valves, people are born with only two cusps and over their lifetime, they are more prone to developing narrowing of the valve (“aortic stenosis”), with a significant probability of needing aortic valve replacement during their lifetime. The idea of screening and surveillance is that any narrowing or malfunction of the aortic valve can be picked up early, and the person can be referred for surgery more quickly and effectively than if their disease had progressed.

BAV is the most common abnormality of the heart valves, occurring in 1- 2% of the general population and is twice as common in males as in females. Reassuringly, a recent cohort study of patients with BAV found that they have similar survival rates to the normal population. However, “given that serious complications will develop in over a third of patients with BAV, the bicuspid valve may be responsible for more deaths and morbidity than the combined effects of all the other congenital heart defects”. The potential problems are narrowing or leaking of the aortic valve, infective endocarditis and enlargement or “dilatation” of the aorta. In other words, BAV is common, has serious complications and there is a treatment which improves survival (aortic valve replacement). Therefore, BAV is a condition which meets Wilson’s criteria for screening.

I was asked by the lady if her children were at risk of BAV and whether they should be screened. I did not know the exact answer so I looked online with the patient. There is a 30% risk of aortic dilatation or BAV in first degree relatives (parents, children or siblings) of people with BAV. A more recent study showed that 20% of first degree relatives of people with BAV may have undetected BAV themselves. It turns out there are no NICE guidelines or formal UK/European guidelines for whether we should be screening relatives or how we should be doing it.

Interestingly, across the pond, the Americans have guidelines for familial screening and the literature seems to suggest it. Therefore adult children of patients with BAV should have an echocardiogram to check that they do not have a BAV which would mean that they should also be followed up. Valvular heart disease is a bigger health issue than we imagine.

There are four take home messages for me. First, EBM can be done at the bedside-it is meant to be the most practical of clinical sciences. Second, there is no harm as a clinician in saying “I don’t know” and looking it up. Third, sometimes it is the obvious clinical questions which are still unanswered or debatable. Finally, practice can be changed.

Comparative effectiveness research or lack thereof

Peter Gill — Sun, 15 Jan 2012 13:30:13 +0000

An earlier TrustTheEvidence.net blog post on the geometry of evidence described the importance of network meta-analyses. These indirect methods of analysis compare the results from two or more studies that have one treatment in common when comparative effectiveness (CE) research is lacking.

What is comparative effectiveness research? To quote the US Federal Coordinating Council for Comparative Effectiveness Research Report to President Obama in 2009, it is defined as the:

“generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor health conditions in ‘real world’ settings”

Additional studies that compare one drug to placebo are not incredibly useful when we already know they work. The real challenge of evidence-based practice is determining which treatment to use when all ten available drugs are better than placebo. How do clinicians decide which one to prescribe? All too often decisions are built on studies lacking active comparators. This is not high quality care for patients.

A recent study published in PLoS ONE evaluated trials registered in ClinicalTrials.gov that focused on the top 25 topics identified as priority areas by the US Institute of Medicine (e.g. treatment of atrial fibrillation). The authors looked at studies conducted in the US between 2007 and 2010 and determined the prevalence of CE research.

Despite the importance of this research methodology, only 22% of studies were CE studies and their characteristics varied substantially based on the funding source. Primarily industry-funded studies had the shortest duration of follow-up and were more likely to report positive findings compared to studies with any government funding.

As usual, children get left out. Industry-funded studies were less likely to enroll children when compared to government or nonprofit funded trials. The lack of controlled trials in children is already a problem and there may be a perceptions among drug manufacturers that testing drugs in children brings the risk of increased liability.

The authors hypothesise that the increase in CE research will lead to an increase in the number of studies that fail to support new interventions. Not good for big pharma, but why?

First, trials with inactive comparators (i.e. placebo) are more likely to achieve favourable findings. On the contrary, CE studies tend to produce conservative results regarding the superiority of a therapy compared to other active treatments.

Second, industry-funded the majority of drug and device CE studies meaning that most were designed and conducted by the company marketing the product. There is substantial evidence that these studies are more likely to report positive findings supporting the use of a product. The PLoS ONE study provides further evidence that even in CE research industry-funded studies were more likely to report an outcome favouring the use of the intervention.

But it’s not all doom and gloom. The US has allocated $1.1 billion to CE research. This added investment of noncommercial funding will be critical to provide unbiased answers and evaluate under-studied populations (e.g. children). It’s about time we provide with stronger evidence.

Research misconduct: 'alive and well'

Carl Heneghan — Thu, 12 Jan 2012 15:51:55 +0000

BMJ research misconduct survey results are released today online and were discussed at the BMJ meeting today on research misconduct.

Sara Schroter, senior researcher, at the BMJ sent an email to 9,036 authors and reviewers on the BMJ database of which 2,782 (31%) replied.

The results show that 13% have witnessed or have had first-hand knowledge of UK based scientists or doctors inappropriately adjusting, eluding altering or fabricating data during their research or for the purpose of publication. Six percent were aware of any cases of possible research misconduct at their institution, that in their view, have not been properly investigated.

Rewards and incentives to conduct research occur at the individual, institutional, national and company level, and misconduct occurS at all of these levels. In a previous survey of 3,247 US researchers, 16% admitted to altering design, methodology or results of their studies due to pressure of an external funding source. In addition, researchers involved with industry were more likely to report one or more of ten serious misbehaviours, to have engaged in misconduct and less likely to report financial conflicts.

As the BMJ survey shows research misconduct is 'alive and well'.

BMJ meeting on research misconduct and the need for a 'paradigm shift'

Carl Heneghan — Thu, 12 Jan 2012 12:32:03 +0000

At the BMJ today research misconduct in the UK was discussed amongst academics, journal editors, policy makers and others.

Why does scientific fraud occur? Among the incidents of scientific fraud that David Goodstein has reviewed, three motives are more or less always present. In all the cases individuals were under career pressure, thought they knew what the result would be if they went to all the trouble of doing the work properly, and were in a field in which studies are not expected to be precisely reproducible.

A case of prolonged research fraud by Diederik Stapel in the Netherlands highlights the closed culture that aids such deception: simply misconduct is more likely when there is less scrutiny.

Peter Wilmhurst, in the morning, talked about the case of Eastell who was suspended from Sheffield University, whislt Professor Clara Gumpert of the Karolinska Institute talked about the case of Suchitra Holgersson: a Karolinska scientist who tried to mislead with false documents.

Iain Chalmers talked about the extensive problems of research that remains unpublished “50% of results remain unpublished.” As far back as 1990, in JAMA, Chalmers published on this exact topic:

“Substantial numbers of clinical trials are never reported in print, and among those that are, many are not reported in sufficient detail to enable judgments to be made about the validity of their results. Failure to publish an adequate account of a well-designed clinical trial is a form of scientific misconduct that can lead those caring for patients to make inappropriate treatment decisions.”

Fiona Godlee, editor of the BMJ, is instrumental in the BMJ's ongoing commitment to identifying and reporting on research misconduct. She spoke recently on the importance and relevance of this exact issue on the BBC: should all medical research be published?

Who can sort the problem out? Journals and their editors are not in a position to be the custodians of integrity. “Editors are not the individuals to investigate cases of research misconduct and the responsibility lies with the institution,” said Elizabeth Wager, chair of the committee on publication ethics. COPE as it is known is a forum for editors and publishers of peer-reviewed journals to address aspects of publication ethics. It also advises editors on what to do in cases of research and publication misconduct.

The morning meeting also discussed policies in the US, Sweden and Germany and their different approaches to research misconduct. It seems there is alot of it going on at the professorial level but also within Phds. Watch out for the BMJ survey coming this afternoon on research misconduct in the UK amongst clinical researchers. I bet it shows there is substantial misconduct going on. It seems to me the incentives are so great for academic to publish, or not in some cases, that it will be a hard problem to solve.

Thomas Kuhn, in 1962 wrote, scientific advancement is not evolutionary, but is a "series of peaceful interludes punctuated by intellectually violent revolutions", and in those revolutions "one conceptual world view is replaced by another". What he referred to as a 'paradigm shift.' A shift that is needed to force action and find solutions to research misconduct.

Weighing up benefit and harm -net clinical benefit and subgroup analysis

Ami Banerjee — Fri, 06 Jan 2012 16:59:49 +0000

The Hippocratic oath originally included the harm and good that doctors and their prescribed treatments can cause. The biggest challenge in today’s clinical practice is not much different. With increasing numbers of trials of different drugs in different patient groups with different comparison groups, how are patients and doctors ever going to see the wood from the trees? How do we make judgments about which drug to use in which situation?

NICE was set up in 1999 in order to help in these difficult matters. Broadly speaking, it looks at current trial evidence and uses the metrics of “cost-effectiveness” to decide whether to fund drugs and treatments in the NHS. It uses “quality-adjusted life years” (the ‘QALY') to measure effectiveness and then calculates the cost per QALY gained for a given drug. A drug must be effective in treating disease but the cost of the benefit must be below a certain threshold, usually £20000-30000 per QALY gained

One problem is that in trials, we tend to focus on benefits and not harms. Another problem is that the performance of drugs in different patients, even for simple characteristics like age and sex and poorly defined in many trials. Even more importantly, trials often do not report their outcomes based on the disease risk of the patients involved. Therefore we end up “painting all patients with one brush”. This has obvious problems. Cost effectiveness analysis is only as good as the trials which are studied and if those trials do not report outcomes (good and bad) properly, then analysis is difficult.

Atrial fibrillation (AF) is a heart rhythm problem which causes increased risk of stroke. Warfarin has been established as a safe treatment for over 50 years and reduces risk of stroke. However, it does lead to increased risk of bleeding, including intracerebral bleeds. Therefore, a way of quantifying the overall benefit of warfarin is to directly weigh up the risk of stroke and the risk of intracerebral bleeds as a “net clinical benefit”, as proposed by Singer and his colleagues in 2009. They reported that “Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category.” In other words, we should use the drug in the patients with the highest chance of benefit from the drug, or the highest chance of the adverse outcome (intracerebral bleeds).

Currently 3 new drugs (dabigatran, apixaban and rivaroxaban) have been evaluated in trials as alternatives to warfarin in the setting of AF. Each of these trials looks at different patients and uses different comparisons. In a recent analysis, we used data from the Danish National Patient registry to work out the net clinical benefit of these drugs at different levels of risk of stroke (potential benefit) and bleeding (potential harm) compared with warfarin. We also calculated the number of patients needed to treat and harm for each drug at each level of risk. Although, this is a modelling exercise, this type of analysis is needed in order to look at all the drugs side by side, using the best evidence we currently have. This idea of “net clinical benefit” could also be used in other disease areas in order to quantify to both health professionals and patients how good or bad a treatment is.

The truth, the whole truth, and ‘nocebo’ effects

Dr Placebo — Wed, 28 Dec 2011 18:58:50 +0000

Good practice demands that doctors inform their patients about both known and suspected side effects of any medication they prescribe. (In ethics-speak this is because of the requirement to respect patient autonomy.) On the other hand, the very act of providing information about side effects can produce negative effects (these are called ‘nocebo’ effects)! For example in a trial of a drug for unstable angina, patients were divided into two groups. The first group was given a statement outlining possible gastrointestinal (GI) side effects, and the second was not. Six times as more patients in the first group experienced subjective GI side effects.

How can doctors respect patient autonomy by revealing all information about side effects, yet avoid doing harm by causing the very side effects they describe? One answer is to give the information in the right way. We all know people who give negative feedback in a way that tends to increase anxiety. Others give the same information to evoke positive responses. Good teachers, coaches, and doctors all know how to frame information constructively.

Another solution is to ask patients. Some patients do not want to be burdened with details of all known and suspected side effects (serious side effects do, of course, need to be revealed). In these cases we can respect patient autonomy and withhold some information because the patient requested to be (partially) ignorant. Other patients do want to know about each and every side effect, in which case there may be little choice other than to reveal them, albeit in the right way.

So what’s the take home message? Tell the whole truth that the patient wants to hear and nothing but the truth in a way that will maximize benefit and minimize harm.

Poisonous poinsettias, harmful holly and malicious mistletoe: what's the evidence?

Peter Gill — Fri, 23 Dec 2011 14:33:23 +0000

The recent post on whether Christmas is bad for you inspired further questions on the evidence behind holiday season myths. There is a common misconception that poinsettias (Euphorbia pulcherrima for the botanists) are poisonous. Grandparents tell stories to new parents that they must be vigilant to ensure that children don’t ingest the plant’s leaves.

But what is the evidence?

A study published in 1996 in the American Journal of Emergency Medicine sought to provide an answer. The authors evaluated 849,575 plant exposures reported to the American Association of Poison Control Centers. Poinsettia exposures accounted for 22,793 cases, or nearly 3%, of which nearly all occurred in December and January. Not surprisingly, 94% of poinsettia exposures were in children.

But were they poisonous? No. None were fatal. In fact, only 4% of patients required treatment in a health care facility and fewer than 7% developed toxicity. Most reactions were mild - children that ingested leaves may experience diarrhea and vomiting or have an allergic reaction to the skin.

Poinsettias are not toxic. They don’t stalk family homes waiting for the opportune time to poison children with their attractive red leaves. Children that accidentally ingest poinsettia leaves rarely require treatment. In fact, the real concern is that they may be a choking hazard.

Well what are the real hazards around Christmas time? The Children's Hospital of Philadelphia website highlights the harms that children need to worry about. An unsuspecting culprit took the top spot: alcohol. Alcohol is a serious hazard in children that can lead to major health problems if ingested by children, even in small quantities. Be wary of leaving empty glasses around the house that could break and be ingested by children.

Similar to alcohol if you are in a cold enough climate, windshield washer fluid and antifreeze are serious hazards. The sweet tasting liquid that looks like Kool-Aid can lead to blindness, seizures, heart-rhythm changes and even death if ingested.

Other quintessential botanical Christmas symbols that are poisonous: holly. A handful of berries from the Illex opaca shrub can produce nausea, vomiting, diarrhea and drowsiness in children. The toxicity of kiss causing mistletoe is not supported by the evidence with most cases having a similar outcome as with poinsettia exposure. But with all substances, beware of large amounts.

Be on the look out for disc batteries (coin shaped circular ones) that can be a choking hazard if swallowed. If they become stuck in the esophagus or stomach, they can begin to leak their caustic contents and cause severe burns.

Irrespective of the hazard, most children swallow these objects when they are left unattended. When enjoying the holiday season this year, keep an eye on the curious children putting objects in their mouth and dispel the old urban myths that lack evidence. Happy Holidays.

Is Christmas bad for you?

Kamal Mahtani — Tue, 20 Dec 2011 22:34:06 +0000

Ah, the festive season. One of my favourite times of year: all the family around, food, a bit of time off work, food, the presents, food, The Queen’s speech, food etc. A wave of emotion floods all my senses at the mere thought.

But can Christmas be bad for your health?

First guilty thoughts go to the waist line. So how much weight do we put on during the festive period? In answering that question I came across an observational study in the British Medical Journal from 1985. In it 22 healthy adults and 13 Type 2 diabetics were weighed one month before and one month after Christmas. All participants had an increase in weight which was on average 1.7lbs (0.8kg). The authors suggested that this came from an additional 6000 kcal they ingested over that period. They also found a slight but significant increase in fasting triglyceride and cholesterol concentrations. Although they reassuringly conclude that the results from their study were unlikely to affect any future Christmas.

Slightly more recently, a prospective cohort study published in the New England Journal of Medicine in 2000 suggested we probably don’t put on as much weight as we think we do over the festive period. In the study 195 adult volunteers were weighed at intervals before and after the holiday season, which included the Thanksgiving weekend. The volunteers gained an average of 0.8lb (0.4kg) during the six weeks between Thanksgiving and New Year's Day, which was far less than what they thought they had put on, which was nearer 5lbs (2.3kg).

So perhaps things aren’t so bad then? Not quite. It’s also about what we eat. There is now little doubt of the role that high salt consumption has in raising blood pressure and therefore increasing the chances of having a heart attack or stroke. The Government had set a target to reduce the salt intake of the population to 6g per person per day by 2010. In reality we probably consume more like 9g per day. Apparently it’s worse at Christmas! A survey this month from the Consensus Action on Salt&Health (CASH) found that an average Christmas day of pre-lunch snacks, canapés and a three course Christmas dinner could contain as much as 15.7g of salt. Admittedly the main culprits are processed foods. The survey makes reference to the fact that a significant proportion of salt consumed could be reduced by simply preparing your own vegetables and avoiding adding salt during the cooking. Likewise choosing the low salt equivalents, such as with crisps, may halve your salt consumption. Or how about a Yorkshire Wensleydale with apricot instead of a Creamy Blue Stilton this year? Again half the salt level.

So am I suffering from “Bah! Humbug syndrome”? Far from it! I fully intend to enjoy the holiday season with all of the above. I’ll just keep one eye on how tight my belt feels and perhaps think a little before that second portion.

Happy Christmas.

Emergency contraception: emotion, evidence and bubble gum

Peter Gill — Sun, 18 Dec 2011 12:30:31 +0000

Earlier this year, the FDA recommended that emergency contraception, or Plan B, should be available without prescription to girls under 17 as it is currently available by prescription only to this age group. In an unprecedented move, the US Health and Human Services secretary Kathleen Sebelius vetoed the FDA's recommendation to make Plan B available without prescription to all women of childbearing age in the US. Mr. Obama said the secretary felt a 10- or 11-year-old should not be able to buy emergency contraception “alongside bubble gum or batteries."

What is Plan B or emergency contraception? Plan B is a pill that consists of the hormone progestin that works by preventing an egg from being fertilised. It must be used within 120 hours after unprotected sex, is safe and effective with few side effects and none dangerous.

Unlike some misconceptions, the availability of emergency contraception dose not change rates of sexual activity or increase the frequency of unprotected sex among adolescents.

Unintended pregnancies are an emotional and controversial issue, invoking deep-rooted religious, political and ideological beliefs. The US has one of the highest rates of unintended pregnancies with nearly half of all pregnancies unintended. In particular, adolescent birth rates in the US are much higher than rates in other developed countries.

Side stepping the issue of induced abortion, what is the effect of unintended pregnancy on women? A recent Lancet editorial discussed the results of a comprehensive review into the mental health outcomes of women after having an induced abortion. The key study finding was that having an unwanted pregnancy leads to an increased risk of mental health problems, not having an induced abortion.

The US should be leading the battle to reduce unintended pregnancies. Indeed the American Academy of Pediatrics (AAP) “encourages abstinence plus comprehensive sexuality education as the best way to help prevent unintended pregnancy and sexually transmitted diseases.” Further, they support the availability of emergency contraception, or Plan B, for adolescents.

Given that only 20-25% of health care providers discuss emergency contraception with adolescents, the restriction of Plan B to prescription only to adolescents under 17 seems a major barrier to access.

What is the likelihood that a 15-year-old who had unprotected sex is going to get a prescription for Plan B? She will be able to purchase acetominophen (i.e. Tylenol or Paracetamol) without a prescription, a medication that can potentially cause fatal liver damage and lead to liver failure if used inappropriately, yet she cannot purchase Plan B to prevent an unintended pregnancy.

Rather than rely on evidence, emotion wins. But the real loser are adolescents under 17 who may face life-long mental health problems. When emotion wins, we all lose.